rs879254910

Positions:

• chr19-11113633-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1457G>A (p.Ser486Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 October 2024.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v4.1.0).BP4: REVEL = 0.297. It is below 0.5, splicing evaluation needed.Functional data on splicing not available.A) Not on limitsB) Does not create a DeNovo AG or GTC) There is no GT or AG nearby.Variant is not predicted to alter splicing. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585463/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.59

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1457G>A	p.Ser486Asn	missense_variant	10/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1457G>A	p.Ser486Asn	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 01, 2019

This missense variant (also known as p.Ser465Asn in the mature protein) replaces serine with asparagine at codon 486 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypercholesterolemia, familial, 1 Benign:1

Likely benign, criteria provided, single submitter

literature only

LDLR-LOVD, British Heart Foundation

Mar 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.52	N;.;.;.;.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.26	T;T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T;T
Polyphen		0.024	B;.;.;.;.;.
Vest4		0.19
MutPred		0.84		Loss of catalytic residue at H485 (P = 0.147);Loss of catalytic residue at H485 (P = 0.147);.;.;.;Loss of catalytic residue at H485 (P = 0.147);
MVP		1.0
MPC		0.20
ClinPred		0.43	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879254910; hg19: chr19-11224309;